Update on the treatment of metastatic renal cell carcinoma

Abstract

Metastatic renal cell cancer (mRCC) management has undergone a paradigm shift in recent decades. The first revolution came with the emergence of vascular endothelial growth factor inhibitors; there was a second wave with the unprecedented success of checkpoint inhibitors, and then the latest approach, which is becoming the new care standard in mRCC, of combining these two strategies in different ways. Updated results of Checkmate-214 after 42 mo of follow-up were consistent with previously published results showing the superiority of nivolumab/ipilimumab over sunitinib in progression free survival (PFS), overall survival (OS), and objective response rate (ORR) in intermediate and high-risk patients. However, several studies presented at the American Society of Clinical Oncology 2020 suggested that the best place, and so far, the only one for nivolumab/ipilimumab is the frontline setting. The update on Keynote-426 after 23 mo of follow-up showed no superiority of pembroli-zumab/axitinib over sunitinib in favorable-risk mRCC, suggesting that it should no longer be the first line of choice in low-risk patients. Finally, the phase III Checkmate 9ER trial results revealed the superiority of nivolumab/cabozantinib vs sunitinib in PFS, OS, and ORR, providing a new first-line option among all International Metastatic RCC Database Consortium risk patients. Some phase II clinical trials also presented this year showed promising results with new combination therapies such as nivolumab/sitravatinib, cabozantinib/atezolizumab, and lenvatinib/pembrolizumab, providing promising grounds upon which to start phase III studies. In addition, other works are using novel therapeutic agents with different mechanisms of action, including telaglenastat (a glutaminase inhibitor), entinostat [an inhibitor of histone deacetylases (HDACs)], and olaparib and talazoparib, poly(ADP-ribose) polymerase inhibitors widely used in other tumors. However, some questions regarding mRCC management still need to be addressed, such as head-to-head comparisons between the current options, treatment sequencing, non-clear cell mRCC, and the role of biomarkers to ascertain the best treatment choice.

Elucidation and Regulation of Tyrosine Kinase Inhibitor Resistance in Renal Cell Carcinoma Cells from the Perspective of Glutamine Metabolism

“…Although TKIs are an effective treatment for RCC, there has recently been a revolutionary development of ICIs [ 14 ]. Despite the development of RCC therapy such as the combination of TKI plus ICIs or dual ICIs, TKIs are still one of the most prominent drugs.…”

“…Recently, regulating glutamine metabolism has become key to overcoming TKI-resistant RCC in the era of combination therapies [ 11 , 12 , 13 ]. However, the anticancer effect against TKI-resistant RCC [ 14 ] and the mechanism of antitumor effects by regulating glutamine metabolism remain unclear [ 15 ].…”

Ketorolac modulates Rac-1/HIF-1α/DDX3/β-catenin signalling via a tumor suppressor prostate apoptosis response-4 (Par-4) in renal cell carcinoma

“…Since multiple pathways are dysregulated in cancer, hence drugs targeting different pathways and their combinations may decrease the chances of cancer resistance, thereby improve outcomes. Other works are using novel therapeutic agents with different mechanisms of action, including telaglenastat (a glutaminase inhibitor), entinostat (HDAC inhibitor) and olaparib, talazoparib (poly (ADP-ribose) polymerase inhibitors) widely used in other tumors 33 . Eventually the goal of treatment, even in the metastatic setting, is cure and/or long-term survival.…”

Recent advances in epigenetic anticancer therapeutics and future perspectives

“…The combinations of epigenetic drugs and immune-checkpoint inhibitors were demonstrated effective for the treatment of cancers which were refractory or resistant to ICB, both in preclinical and clinical studies. The combinations of HDACi and ICB have received favorable clinical effect in the clinical trials, such as vorinostat and pembrolizumab (anti-PD-1 antibody) for the treatment of ICB-resistant metastatic NSCLC ( Rodriguez et al, 2020 ), entinostat and pembrolizumab for the treatment of microsatellite-stable CRC ( Medina Lopez et al, 2022 ). It is worth mentioning that the combinations of epigenetic drugs and immune-checkpoint inhibitors are usually well tolerated without severe toxic effects, which are superior to the combinations with targeted therapy.…”